Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage

Area of Science:

• Immunology
• Cell Biology
• Pulmonary Medicine

Background:

• Tissue fibrosis, a significant cause of mortality, involves matrix protein deposition by activated mesenchymal cells.
• Macrophages infiltrate fibrotic tissues, yet the specific roles of macrophage subgroups in fibrogenesis remain unclear.
• Understanding macrophage heterogeneity is crucial for elucidating fibrosis mechanisms.

Purpose of the Study:

• To characterize macrophage heterogeneity in bleomycin-induced lung fibrosis using single-cell RNA sequencing (scRNA-seq).
• To identify specific macrophage subgroups that contribute to the fibrotic process in vivo.
• To explore the translational relevance of identified macrophage populations in human fibrotic lung disease.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) was employed to analyze macrophage populations in mouse models of lung fibrosis.
• A computational framework (SingleR) was utilized for annotating scRNA-seq data by referencing bulk transcriptomes.
• Macrophage subclusters were identified, focusing on disease-associated transitional populations.

Main Results:

• scRNA-seq revealed a distinct subgroup of CX3CR1+SiglecF+ transitional macrophages within the fibrotic lung niche.
• These transitional macrophages exhibit an intermediate gene expression profile between monocyte-derived and alveolar macrophages.
• Functional analysis indicated a profibrotic role for these transitional macrophages in vivo.
• Human orthologs of genes expressed by these macrophages were found upregulated in idiopathic pulmonary fibrosis patient samples.

Conclusions:

• A novel pathological subgroup of transitional macrophages has been identified as critical drivers of the fibrotic response.
• These transitional macrophages are essential for the fibrotic response to injury in the lung.
• The findings highlight transitional macrophages as a potential therapeutic target for treating tissue fibrosis, including idiopathic pulmonary fibrosis.